Although efficacy of therapeutic treatments is critically dependent upon mechanism of action of the agent(s) used, other factors are often instrumental in eliciting an optimal response. Tolerable dose and time of administration relative to onset of disease are other key considerations. Additionally, there are a number of complex issues involving pharmacokinetic and pharmacodynamic characteristics that can also be significant in therapeutic response. Over the years many studies have been carried out with a vast array of therapeutic agents in an effort to establish optimal strategies for drug delivery. Over time, more and more drug regimens for virtually all types of diseases have been designed to involve combination therapies; in some instances, combinations are used to improve efficacy by combining drugs that have the same or different disease targets; in others, drugs with different mechanisms of action may act synergistically; and in still others, combination therapies might involve one or more drugs that act directly on the disease state together with one or more agents that have a beneficial effect, such as reduction of pain and/or protection from side effects of organs not directly involved in the disease and/or promotion of desirable activities by natural defensive mechanisms, notably the immune system. Such disparate drugs with disparate roles in disease treatment often differ dramatically with respect to chemical nature and thus drug delivery issues in combination therapy can be very challenging.
Strategies involving the use of miniaturized vehicles that can encapsulate drugs in such a way as to allow for controlled release have shown promise as a way to optimize drug delivery characteristics. Such systems offer the possibility of successful treatment and control of many diseases with drugs whose systemic half-lives and biodistribution are critical. Because of the diverse chemical nature of different drugs, there is a distinct advantage in the design and availability of a miniaturized vehicle that can usefully control drug release in a manner that is agnostic to the chemical nature of the drug.
Particulate vaccines are promising technologies for creation of tunable prophylactics and therapeutics against a wide variety of conditions. Vesicular and solid biodegradable polymer platforms, exemplified by liposomes and polyesters, respectively, are two of the most ubiquitous platforms in vaccine delivery studies. Immunization with poly(lactide-co-glycolide) (PLGA) nanoparticles elicits prolonged antibody titers compared to liposomes and alum. The magnitude of the cellular immune response is highest in animals vaccinated with PLGA, which also shows a higher frequency of effector-like memory T-cell phenotype, leading to an effective clearance of intracellular bacteria. The difference in performance of these two common particulate platforms is shown not to be due to material differences but appears to be connected to the kinetics of antigen delivery. Liposomes are easily modified for encapsulation of small hydrophilic molecules, and even proteins. However, the stability of these formulations and the release profiles of encapsulated agents are not easily controlled. Biodegradable solid particles, on the other hand, such as those fabricated from poly(lactic-co-glycolic acid) (PLGA), are highly stable and have controllable release characteristics, but pose complications for facile encapsulation and controlled release of therapeutic cytokines or for combinatorial delivery. To overcome these limitations, hybrid platforms that integrate features of different materials can offer advantages in combinatorial encapsulation and delivery. Such systems have been demonstrated based on a core-shell methodology in which an organic or inorganic mesoporous or nanoporous core entrapping molecules of interest is coated with lipids or polymers. These hybrid systems can enhance encapsulation and release of a wide variety of agents, such as small molecule drugs, proteins and nucleic acids, while promoting favorable pharmacokinetics and biodistribution of the encapsulant.
Hybridized systems, as such, are clearly attractive drug delivery alternatives and have been explored in different studies. Such systems can be engineered with a fluid biological bilayer that enhances their circulation or potential for targeting while enabling the delivery of agents of different physical properties. Several core-shell hybrid systems have been demonstrated for this purpose and indeed offer exciting new possibilities for combinatorial delivery that can work in cancer therapy.
It is clear that the rate of release of bioactives, especially in the vaccine field, is critically important to the function, not just which bioactives are incorporated. The complexity associated with delivery of two different agents, such as an antigen and an immunomodulator, makes it more difficult to find a delivery vehicle that allows for controlled release of the agents at different rates. This is particularly the case where the properties of the two agents are different, such as when one is hydrophobic and one is hydrophilic, or one is high molecular weight and the other is low molecular weight. Even though it is possible to provide particles that differ in chemical properties, it is difficult to ensure that the agents are released at the correct time, for example, without having to diffuse from the core through the shell, where the core is hydrophobic and the shell is hydrophilic (or vice versa) and the properties of the agents lead them to migrate into another area of the delivery device rather than out of the device, or, for example, where one agent is very low molecular weight and tends to diffuse out rapidly and the other agent is very high molecular weight and tends to diffuse out extremely slowly.
It is therefore an object of the present invention to provide means for delivery of two or more pharmaceutical agents at different rates, especially agents with different chemical properties and/or molecular weights.